The long-term objective of this project is to gain more insight into the processes that govern the release and subsequent removal of the adrenergic neurotransmitter in cardiac tissues. The major emphasis of this application will be on the physical processes (true diffusion and bulk transport) that remove norepinephrine (NE) from the cardiac interstitium. The specific aims of the proposed experiments are to determine the influence of changes in heart rate on the removal of neurally released NE, to compare these effects in animals with the neuronal amine uptake mechanism intact with those in animals with the uptake mechanism suppressed, and to determine the mechanisms by which changes in heart rate alter the removal of transmitter. We will induce complete atrioventricular block in anesthetized dogs so that we can pace the heart artificially over a wide frequency range. We will stimulate the cardiac sympathetic nerves with trains of constant frequency pulses. We will measure (a) the steady-state ventricular inotropic responses and NE overflows into the coronary sinus blood during tonic sympathetic stimulation, and (b) the decays of those responses immediately after cessation of sympathetic stimulation. We will assess the role of diffusion in the washout of NE from the cardiac interstitium by cannulating the left main coronary artery and varying the arterial blood flow. We will assess the role of bulk transport by holding coronary arterial blood flow constant. We will vary pacing frequency in one group of experiments and will vary contractile strength in another group. In this latter group, total heart-lung bypass will be instituted, and contractile strength will be varied by inserting a fluid-filled balloon into the left ventricular cavity and altering the fluid volume. Knowledge of the mechanisms of NE dissipation are important, because the rate of dissipation is a determinant of the NE concentration in the cardiac tissues, and hence is a critical determinant of cardiac performance.